Sepsis and Septic shock

By Habtamu Bayih(MD)
 INTRODUCTION

• Sepsis
– Is a clinical syndrome that complicates severe infection
and is characterized by systemic inflammation and
widespread tissue injury.
• In this syndrome
– tissues remote from the original insult display the
cardinal signs of inflammation, including
• Vasodilation
• Increased microvascular permeability, and
• Leukocyte accumulation.
 INTRODUCTION…

• Current beliefs regarding the onset and progression of

sepsis center upon
• a "dysregulation" of the normal response, with a massive
and uncontrolled release of proinflammatory mediators
creating a chain of events that leads to widespread tissue
injury.
• Bacteremia
– Presence of bacteria in blood, as evidenced by positive blood
cultures

• Septicemia
– Presence of microbes or their toxins in blood

• SIRS (Systemic inflammatory response syndrome)

– A systemic level of inflammation that may or may not be due to
infection, generally manifested as a combination of vital sign
abnormalities including fever or hypothermia, tachycardia, and
tachypnea.

• Severe SIRS
– When at least 1 major organ system fails in the setting of SIRS.
 Definitions…
• Sepsis
– SIRS that has a proven or suspected microbial etiology
• Severe Sepsis
– Severe SIRS which is secondary to infection.
• Septic Shock
– Sepsis with hypotension (arterial blood pressure <90
mmHg systolic, or 40 mmHg less than patient's normal
blood pressure) for at least 1 h despite adequate fluid
resuscitation; or
– Need for vasopressors to maintain systolic blood
pressure 90 mmHg or mean arterial pressure 70
mmHg.
 Definitions…

• Refractory septic shock

– Septic shock that lasts for >1 h and does not respond
to fluid or pressor administration
• MODS (Multiple organ failure)
– The presence of altered function of more than one
organ in an acutely ill patient, which requires
intervention in order for the patient to maintain
homeostasis (e.g. mechanical ventilation,
hemodialysis).
 Definitions…

• Primary MODS
– is used when the organ failure is attributable to the
initial insult itself (ARF following rhabdomyolysis).
• Secondary MODS
– occurs when the organ failure is a result of the host
response to the initial insult (e.g. ARDS in pancreatitis).
 Definitions…

• Diagnostic Criteria:
• SIRS
– Requires 2 of the following:
– a. Temp >38.3° or <36.0° C
– b. Tachypnea (RR>20 )
– c. Tachycardia (HR>90, in the absence of intrinsic heart
disease)
– d. WBC > 12,000/mm3 or <4,000/mm3 or >10% band
forms on differential
 Definitions…
• Severe SIRS
– Must meet criteria for SIRS, plus 1 of the following:
– a. Altered mental status
– b. SBP<90mmHg or fall of >40mmHg from baseline
– c. Impaired gas exchange (PaO2/FiO2 ratio<200-250)
– d. Lactic acidosis (pH<7.30 & lactate > 1.5 x upper limit
of normal)
– e. Oliguria or renal failure (<0.5mL/kg/hr)
– f. Hyperbilirubinemia
– g. Coagulopathy (platelets < 80,000-100,000/mm3, INR
>2.0, PTT >1.5 x control, or elevated fibrin degredation
products)
 Definitions…

• In order for a pathophysiologic state to be

referred to as “sepsis”,
– there must be clinical evidence of infection in addition
to the above criteria
– e.g. positive cultures, perforated viscus, WBCs in a
normally sterile fluid, radiographic evidence of
pneumonia, or a syndrome associated with unusually
high rate of infection such as ascending cholangitis.
 Definitions…

• Venn diagram displaying the various terminology

surrounding sepsis and SIRS:
 SIRS Continuum

SEPSIS PANCREATITIS

SEVERE
SEPSIS

SIRS BURNS
INFECTION SEPTIC
SHOCK

TRAUMA

OTHER
 Etiology
• Sepsis can be a response to any class of microorganism
• Microbial invasion of the bloodstream is not essential,
since local inflammation can also elicit distant organ
dysfunction and hypotension
• Blood cultures yield bacteria or fungi in only –20–40% of
cases of severe sepsis and 40–70% of cases of septic
shock
• Individual gram-negative or gram-positive bacteria
account for –70% of these isolates; the remainder are
fungi or a mixture of microorganisms
 Etiology…

– In patients whose blood cultures are negative, the

etiologic agent is often established by
• culture or microscopic examination of infected material
from a local site;
• specific identification of microbial DNA or RNA in blood or
tissue samples is also used.
• In some case series, a majority of patients with a clinical
picture of severe sepsis or septic shock have had
negative microbiologic data.
 Etiology…
• Gram-negative bacteria most common
– Escherichia coli
– Pseudomonas aeruginosa
– Rickettsiae
– Legionella spp.
• Gram-positive bacteria
– Enterococcus spp.
– Staphylococcus aureus
– Streptococcus pneumoniae
• Fungi (Candida species)
• Viruses
Etiology…
Etiology…
 Etiology…
• Microorganisms involved in sepsis syndrome in
relation to host factors
 Etiology…
• The common infections causing septic shock are
– Pneumonia
– Peritonitis
– Pyelonephritis
– Abscess (especially intra-abdominal)
– Primary bacteremia
– Cholangitis
– Cellulitis
– Necrotizing fasciitis, and
– Meningitis
• Nosocomial pneumonia is the most common
cause of death from nosocomial infection.
Etiology…
 Epidemiology
• Severe sepsis is a contributing factor in >200,000 deaths
per year in the United States, 10th leading cause of death

• The incidence of severe sepsis and septic shock has

increased over the past 30 years, and the annual number
of cases is now >700,000 (~3 per 1000 population).
• Approximately two-thirds of the cases occur in patients
with significant underlying illness.
• Sepsis-related incidence and mortality rates increase with
age and preexisting comorbidity
• A primary site of infection cannot be established in 10% of
patients with severe Sepsis/SIRS
Risk Factors for Developing Sepsis:

– Extremes of age – Diabetes

– Indwelling – Cirrhosis
lines/catheters – Altered mental status
– Immunocompromised
– Male sex
states
– Genetic predisposition
– Malnutrition
– Alcoholism
– Malignancy
Natural history of the sepsis process
 Pathophysiology:

• Approximately 70-80% of all patients with septic shock will

have a specific bacterial agent identified.
• Although the distribution is approximately 50% gram
negative, 50% gram positive, a further breakdown is not
relevant as all patients will require broad-spectrum
antibiotics regardless.
• The severity of the sepsis syndrome is not dependent on
the inciting organism (or even on whether an organism
exists at all, as in cases of severe SIRS), but rather on the
host response to the triggering event.
 Pathophysiology…

• Although inflammation is essential to host response

against infection, SIRS results from a dysregulation of the
normal response, with massive, uncontrolled release of
pro-inflammatory mediators.
• In simplest terms, the current model of how SIRS
develops, involves a multistep cascade in which an initial
trigger leads to the production of a limited number of early
mediators, followed over several hours by a larger
number of secondary mediators
Pathophysiology…
 Pathophysiology…

• Mechanism of the development of hypotension in

SIRS/sepsis
• Vasodilation
– Activation of ATP-sensitive K+ channels in the vascular
smooth muscle
– Increased synthesis of NO as a result of increased
levels of the enzyme, inducible NO synthase
– Deficiency of vasopressin
 Pathophysiology…

• Intravascular Volume Depletion

– Increased capillary permeability leading to third-spacing
of fluid
– Concurrent volume loss from vomiting or diarrhea
Pathophysiology…
Pathophysiology…
 Pathophysiology…
• Inflammatory responses to sepsis
– Gram-positive and gram-negative bacteria, viruses, and fungi
have unique cell wall molecules called pathogen-associated
molecular patterns that bind to pattern recognition receptors
(called Toll-like receptors [TLRs]) on the surface of immune cells.
– The lipopolysaccharide (LPS) of gram-negative bacilli binds to
LPS-binding protein–CD14 complex.
– The peptidoglycan of gram-positive bacteria and the LPS of gram-
negative bacteria bind to TLR-2 and TLR-4, respectively.
– TLR-2 and TLR-4 binding activates intracellular signal transduction
pathways that lead to the activation of the cytosolic transcription
factor nuclear factor kappa B (NFκB)
 Pathophysiology…
– Activated NFκB moves from the cytoplasm to the nucleus, binds to
transcription start sites, and increases the transcription of
cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β
(IL-1β), and interleukin-10 (IL-10).
– TNF-α and IL-1β are pro-inflammatory cytokines that activate the
adaptive immune response but also cause both direct and indirect
host injury.
– IL-10 is an anti-inflammatory cytokine that inactivates
macrophages and has other anti-inflammatory effects.
– Sepsis increases the activity of inducible nitric oxide synthase
(iNOS), which increases the synthesis of nitric oxide (NO), a
potent vasodilator.
 Pathophysiology…

– Cytokines activate endothelial cells by upregulating adhesion

receptors such as intercellular adhesion molecule (ICAM), and
they injure endothelial cells by the activation and binding of
neutrophils, monocytes, macrophages, and platelets to endothelial
cells.
– These effector cells release mediators such as proteases,
oxidants, prostaglandins, and ICAM leukotrienes.
– Cytokines also activate the coagulation cascade.
Pathophysiology…
 Pathophysiology…
• Pro-coagulant response in sepsis
– Sepsis initiates coagulation by activating the endothelium to
increase tissue factor.
– Activation of factors Va and VIIIa leads to the formation of
thrombin-α, which converts fibrinogen to fibrin.
– Fibrin binds to platelets that adhere to endothelial cells, forming
microvascular thrombi.
– Microvascular thrombi amplify injury by the release of mediators
and by microvascular obstruction, which causes distal ischemia
and tissue hypoxia.
– Normally, natural anticoagulants—protein C (PC), protein S (PS),
antithrombin, and tissue factor pathway inhibitor (TFPI)—dampen
coagulation, enhance fibrinolysis, and remove microthrombi
 Pathophysiology…
– Thrombin-α binds to thrombomodulin on endothelial cells and thus
activates the binding of PC to endothelial PC receptor (EPCR).
– PC forms a complex with its cofactor PS. PC binding to EPCR
increases the activation of PC to activated PC (APC).
– APC proteolytically inactivates factors Va and VIIIa and decreases
the synthesis of plasminogen activator inhibitor-1 (PAI-1).
– Sepsis decreases levels of PC, PS, antithrombin, and TFPI.
– Lipopolysaccharide and tumor necrosis factor-α (TNF-α) decrease
thrombomodulin and EPCR, thus decreasing the activation of PC.
– Lipopolysaccharide and TNF-α also inhibit PAI-1, so fibrinolysis is
inhibited.
 Pathophysiology…

HIFα = hypoxia-inducing factor-α; NO = nitric oxide; tPA = tissue

plasminogen activator; VEGF = vascular endothelial growth factor.
Pathophysiology…
Pathogenesis…
 Pathogenesis…

• Endotoxin  stimulation of humoral and cellular immune

systems  activation of complement sequence and
coagulation cascade
• Activation of coagulation cascade activation of
fibrinolytic system DIC
• Complement activation  chemotaxis of PMNs,
degranulation of mast cells, and release of histamine and
inflammatory mediators  increased capillary
permeability
 Pathogenesis…

• INFLAMMATION release of catecholamines and

prostaglandins generalized vasoconstriction
• VASOCONSTRICTION decreased perfusion of vital
organs tissue hypoxia metabolic acidosis
• METABOLIC ACIDOSIS capillary pooling decreased
circulating blood volume decreased venous return
decreased cardiac output
• DECREASED CARDIAC OUTPUT decreased coronary
and cerebral blood flow intractable hypotension, coma,
multiorgan failure DEATH
 Clinical manifestations

Altered mental status

Thermal instability
Cardiac dysfunction
Respiratory compromise
• Bleeding
• Jaundice
• Ileus
• Skin changes
 Differential diagnosis

• Cardiogenic shock
• Hypovolemic shock
• Venous or AF embolism
• Cardiac tamponade
• Hemorrhagic pancreatitis
• Diabetic ketoacidosis
• Aortic dissection
 Diagnostic tests

• Laboratory Test
– WBC decreased, then increased
– HCT variable
– PLT decreased with DIC
– Fibrinogen decreased with DIC
– Fibrin degradation products increased with DIC
– PT, PTT, TT prolonged with DIC
– pH decreased
– Lactic acid increased (poor prognostic factor)
 Diagnostic tests…
• Laboratory Test
– pO2 decreased
– pCO2 increased
– HCO3 decreased
– K+ increased
• Microbiology studies
– Urine culture
– Blood culture
– Culture of peritoneal fluid
– Culture of abscess
– Sputum culture
 Diagnostic tests…

• Imaging studies
– Chest x-ray
– Abdominal films
– IVP
– CT
– MRI
– Ultrasound
• Other diagnostic studies
– ECG
– Right heart catheterization
 Treatment of Sepsis
• Early recognition of the Sepsis syndrome.
• Prompt administration of broad-spectrum
antibiotics.
• Surgical intervention when indicated.
• Aggressive supportive care in intensive care units.
• Steroids
• Tight glycemic control.
• Activated protein C
• Newer therapies.
 Treatment…
• Initial Six Hours
– initiate fluid resuscitation with crystalloid or colloid to achieve
central venous pressure of 12mm Hg (or 15mm Hg if intubated).
– Add dopamine (Intropin) or norepinephrine (Levophed) for
persistent hypotension (mean arterial pressure <65mm Hg).
– Obtain blood, urine, and other appropriate cultures (cerebrospinal
fluid, abscess drainage, catheter tip, tissue, sputum).
– Administer empiric antimicrobial therapy.
– Perform appropriate imaging studies with urgent source control as
indicated and allowed by clinical status; remove potentially
infected foreign bodies.
– All interventions should be undertaken simultaneously and initiated
within 1 hour after making a presumptive diagnosis of sepsis.
 Treatment…
• Subsequent Interventions
–  Maintain glycemic control with a target blood glucose level of less
than 150mg/dL.
– Use unfractionated or low-molecular-weight heparin for
prophylaxis against deep venous thrombosis.
– Use a histamine 2 (H2) blocker or proton pump inhibitor for gastric
ulcer prophylaxis.
– Initiate therapy with dobutamine (Dobutrex) for low cardiac output
in the face of adequate filling pressures.
– Consider therapy with activated protein C (drotrecogin alfa [Xigris])
for patients with an Acute Physiology and Chronic Health
Evaluation (APACHE) II score of 25 or greater.
– Consider therapy with hydrocortisone (Solu-Cortef)[1] for patients
with continued hypotension despite adequate fluid resuscitation
and vasopressors.
 Severe Sepsis:
Initial Resuscitation (1st 6 hours)
 Should begin as soon as the syndrome is
recognized and should not be delayed pending
ICU admission.
 Elevated serum lactate concentration identifies
tissue hypoperfusion in patients at risk who are
not hypotensive.
 Resuscitation Goals

Goals in the first 6 hours:

 CVP: 8-12 mm Hg
 MAP > 65 mm Hg
 Urine output > 0.5 ml/kg/hr
 Central venous (SVC) or mixed venous
oxygen (SvO2) saturation > 70%
 Sepsis Resuscitation Bundle

 In the event of hypotension and/or lactate > 4

mmol/L:
– Administer a minimum of 20 ml/kg of crystalloid (or
colloid equivalent)
– Use vasopressors for hypotension not responding to
initial fluid resuscitation to maintain MAP > 65 mmHg:
1C
 Sepsis Resuscitation Bundle
 If persistent arterial hypotension despite volume
resuscitation (septic shock) and/or initial lactate >
4 mmol/L:
– Recommend insertion of central venous catheter
– Achieve CVP of 8-12 mmHg
• Higher with altered ventricular compliance or increased
intrathoracic pressure
– Achieve ScvO2 of > 70% or SvO2 > 65%
 If ScvO2 remains < 70% after fluid resuscitation
goals are met
• Dobutamine up to 20 µg/kg/min
• Transfusion to maintain Hct 30%
 Fluid Therapy
 Fluid resuscitation with either natural or artificial
colloids or crystalloids.

 Fluid challenge in patients with suspected

hypovolemia may start with > 1000 ml of crystalloids
or 300-500 ml of colloids over 30 mins.

 Rate of fluid administration should be reduced

substantially when cardiac filling pressures (CVP or
PAOP) increase without concurrent hemodynamic
improvement
 Vasopressor Therapy
 Either norepinephrine or dopamine is the first
choice vasopressor agent to correct hypotension
in septic shock.
 Low-dose dopamine should not be used for renal
protection.
 Epinephrine or Vasopressin (0.03 U/min) may be
added in pts with refractory shock despite
adequate fluids and high-dose conventional
vasopressors.
 Inotropic Therapy

 Dobutamine infusion is recommended in the

presence of myocardial dysfunction as suggested
by elevated cardiac filling pressures and low
cardiac output.

 Avoid use of strategy to increase cardiac index to

predetermined supranormal levels.
 Antimicrobial Therapy

• IV antibiotics should be started within the first

hour of recognition of severe sepsis after
appropriate cultures have been obtained.

• Initial empirical antimicrobial therapy should

include one or more drugs that have activity
against the likely pathogens (bacterial or
fungal) and that penetrate into the presumed
source of sepsis.
 Treatment…

• Immunocompetent adult acceptable regimens

include
– (1) piperacillin- tazobactam (3.375 g q4–6h);
– (2) imipenem-cilastatin (0.5 g q6h) or meropenem (1 g
q8h); or
– (3) cefepime (2 g q12h).
– If the patient is allergic to ᵦ- lactam agents, use
• ciprofloxacin (400 mg q12h) or levofloxacin (500–750 mg
q12h) plus clindamycin (600 mg q8h).
– Vancomycin (15 mg/kg q12h) should be added to each
of the above regimens.
 Treatment…
• Neutropenia (<500 neutrophils/L) Regimens include
– (1) imipenem-cilastatin (0.5 g q6h) or meropenem (1 g q8h) or
cefepime (2 g q8h);
– (2) piperacillintazobactam (3.375 g q4h) plus tobramycin (5–7 mg/kg
q24h).
– Vancomycin (15 mg/kg q12h) should be added
• if the patient has an indwelling vascular catheter, has received quinolone
prophylaxis, or has received intensive chemotherapy that produces
mucosal damage; if staphylococci are suspected;
• if the institution has a high incidence of MRSA infections; or if there is a
high prevalence of MRSA isolates in the community.

– Empirical antifungal therapy with an echinocandin (for caspofungin: a

70-mg loading dose, then 50 mg daily) or a lipid formulation of
amphotericin B should be added if the patient is hypotensive or has
been receiving broad-spectrum antibacterial drugs.
 Treatment…
• Splenectomy
– Cefotaxime (2 g q6–8h) or ceftriaxone (2 g q12h) should be used.
– If the local prevalence of cephalosporin-resistant pneumococci is
high, add vancomycin.
– If the patient is allergic to -lactam drugs, vancomycin (15 mg/kg
q12h) plus either moxifloxacin (400 mg q24h) or levofloxacin
(750mg q24h) or aztreonam (2 g q8h) should be used.

• IV drug user
– Vancomycin (15 mg/kg q12h)
 Treatment…

• AIDS
– Cefepime (2 g q8h) or piperacillin-tazobactam (3.375 g q4h) plus
tobramycin (5–7 mg/kg q24h) should be used.
– If the patient is allergic to beta-lactam drugs, ciprofloxacin (400 mg
q12h) or levofloxacin (750 mg q12h) plus vancomycin (15 mg/kg
q12h) plus tobramycin should be used.
 Corticosteroid Therapy
• IV hydrocortisone should be given only to adult
septic shock patients after it has been confirmed
that their BP is poorly responsive to fluid
resuscitation and vasopressor therapy.
 Treatment regimens:
– 100 mg hydrocortisone IV q 8 h
– 100/200 mg bolus of hydrocortisone then 10 mg/h
– 50 mg hydrocortisone IV q 6 h
 Full dose hydrocortisone treatment should be
continued for 5-7 days before tapering assuming
there is no recurrence of signs of sepsis or shock
Recombinant Human Activated Protein C

• Recommended in adult pts with sepsis-induced

organ dysfunction associated with a high risk of
death (APACHE II > 25) or multiple organ failure
and with no contraindications related to bleeding

• Adult patients with severe sepsis and low risk of

death (APACHE II < 20) or one organ failure
should not receive rhAPC
Mechanical Ventilation of Sepsis-
Induced ALI/ARDS

• Nearly all patients with septic shock require

supplemental oxygen, and approximately 80%
require mechanical ventilation.

• Use of mechanical ventilation not only may

improve oxygenation, but the necessary sedation
+/- paralysis may improve organ perfusion by
diverting blood flow away from the diaphragm.
 Mechanical Ventilation of Sepsis-
Induced ALI/ARDS
 Target tidal volume of 6 mL/kg (predicted) body
weight
 Maintain plateau pressures < 30 cm H2O
 Permissive hypercapnia may be required to minimize
plateau pressures and tidal volumes
 May use prone positioning in severe ARDS
 Keep HOB elevated 30-45° to reduce VAP
 Glucose Control
 Recommend that patients with severe sepsis and
hyperglycemia who are admitted to the ICU receive IV
insulin to decrease blood glucose
 Maintain BG < 150 mg/dl using insulin
 Patients on IV insulin should receive a glucose calorie
source and BG be monitored every 1-2h until glucose
values and insulin infusion rates are stable and then every
4h thereafter
 The Others

 Sedation, analgesia and neuromuscular blockade

 Renal replacement therapy
 Bicarbonate therapy
 DVT prophylaxis
 Stress ulcer prophylaxis
 FUTURE STRATEGIES FOR SEPSIS

Lipid A
antagonists

Complement MIF inhibitors

blockers

Apoptosis inhibition HMGB-1 inhibitors

Treatment strategies proven to change
outcome in severe sepsis

• Early goal directed therapy

• Lung protective ventilation

• Appropriate antibiotic coverage

• Activated protein C

• Tight control of sugars 80-100mg/dl

• Steroids
 A clinician, armed with the sepsis bundles, attacks the three heads of severe

sepsis: hypotension, hypoperfusion and organ dysfunction. Crit Care Med 2004;

320(Suppl):S595-S597